This invention lies in the field of systemic and topical treatments of papulosquamous diseases and eczematous diseases.
Papulosquamous diseases are those conditions of the skin characterized by sharply demarcated red scaley patches or plaques that microscopically display acanthosis and hyperkeratosis without spongiosis. Inflammation and hyperproliferation are the key pathophysiologic processes in these diseases. Included among this group of diseases are psoriasis, lichen planus, pityriasis and parapsoriasis.
Eczematous diseases are those inflammatory skin conditions characterized by poorly demarcated scaley, crusty or weeping patches that microscopically display spongiosis. This group of diseases includes seborrheic and atopic dermatitis, contact allergic and irritant dermatitis, dyshidrosis, lichen simplex chronicus, eczema craquele, and patch and plaque stages of cutaneous T cell lymphoma.
Microbial infection by bacteria, fungus or yeast often aggravate, and occasionally cause, the eruption of diseases within both groups. Such organisms also retard therapeutic response.
Various therapeutic formulations for papulosquamous and eczematous diseases are commercially available.
One type of available formulation utilizes the class of compounds known as glucocorticosteroids. These are derivatives of cholesterol which are antiinflammatory and mildly antiproliferative. Despite their status as the mainstay of treatment for these diseases, however, these agents give rise to numerous adverse reactions when used systemically or topically, some of which are irreversible.
Another type are chemotherapeutic compounds, including antimetabolites such as methotrexate and fluorouracil, alkylating agents such as mechlorethamine and carmustine, antibiotics such as bleomycin, and immunosuppressives such as cyclosporin, dapsone and colchicine.
Certain retinoids have proven efficacy against papulosquamous diseases. These include isotretinoin, tretinoin, etretinate and etretin.
Tar compounds with proven efficacy include crude coal tar, liquor carbonis detergens and anthralin.
Antibacterial agents that are effective in killing staphylcoccus, streptococcus and propionobacterium species often produce a therapeutic effect on papulosquamous and eczematous diseases. These include tetracycline, erythromycin, clindamycin, bacitracin, neomycin, chlorhexidine, sulfacetamide, meclocycline, polymixin, colistin and chloramphenicol.
Background information relating to the substances utilized in the present invention is as follows.
Artemisinin (Qinghaosu) and its analogs are the treatments of choice for cerebral or chloroquine resistant malaria or for patients with chloroquine allergy. Artemisinin is a naturally occurring substance, obtained by purification from sweet wormwood, Artemisia Annua. Artemisinin and its analogs are sesquiterpene lactones with a peroxide grouping, and are characterized by very low toxicity and poor water solubility. Artemisinin is known as a humoral immunosuppressive agent which is less active than cyclophosphamide, the latter being one of the major chemotherapeutic agents for carcinomas. Artemisinin stimulates cell-mediated immunity, and yet decreases abnormally elevated levels of polyamine regulatory proteins. It also markedly inhibits nucleic acid and protein syntheses. Further, it affects cellular membrane function and decreases hepatic cytochrome oxidase enzyme system activity. Still further, it is virustatic against influenza and cidal against three groups of pathogenic parasites.
Known analogs of artemisinin which have higher solubility in water are dihydroartemisinin, artemether, artesunate, arteether, propylcarbonate dihydroartemisinin and artelinic acid. Dihydroartemisinin has an antimalarial potency which is 60% higher than that of artemisinin. Artemether and artesunate have antimalarial potencies which are 6 times and 5.2 times, respectively, that of artemisinin. In terms of their ability to inhibit nucleic acid synthesis, dihydroartemisinin, artemether, artesunate, arteether, and propylcarbonate dihydroartemisinin all have 100 times the activity of artemisinin, and protein synthesis is stimulated to an even greater extent by these compounds. Artesunate stimulates the immune system at low doses and inhibits it at high doses. Artelinic acid is the most water-soluble and the most stable of the group. Two of the compounds in this group have been demonstrated to display synergistic activity with doxorubicin (a chemotherapeutic agent) and miconazole (an antifungal agent) in the in vitro killing of Plasmodia Falciparum, the etiologic agent of malaria.
The very low toxicity of these compounds to humans is a major benefit. Artesunate, for example, is twice as safe as artemether and only one-fiftieth as toxic as chloroquinine, the most common antimalarial. The first manifestation of toxicity of these compounds is generally a decreased reticulocyte count. Other manifestations include transient fever, decreased appetite and elevated blood transaminase levels, the latter an indication of hepatotoxicity.
Monocarboxylic acids and their ester and amide analogs are known to inhibit mitochondrial respiratory enzymes of Ehrlich tumor cells in mice. The monoglyceride ester of lauric acid (monolaurin) is particularly effective in inhibiting these enzymes. Monolaurin has potent cytotoxic activity against two leukemia cell lines and stimulates cell mediated immunity. These fatty acids and analogs significantly inhibit human pathogenic virus, fungi, yeast, and gram-positive bacteria growth. Monolaurin is the most potent as a microbial inhibitor. These compounds also are selectively absorbed by abnormally hyperactive cells. They have very low systemic toxicity and are mildly irritating topically to humans. Derivatives of 12-carbon atom length acids, especially monolaurin, have exceptional skin cell and stratum corneum penetration enhancing functions as well as stabilizing activity for other pharmaceutically active compounds.